Carboxylic acid derivatives, their preparation and use

ABSTRACT

PCT No. PCT/EP95/03963 Sec. 371 Date Mar. 27, 1997 Sec. 102(e) Date Mar. 27, 1997 PCT Filed Oct. 7, 1995 PCT Pub. No. WO96/11914 PCT Pub. Date Apr. 25, 1996Carboxylic acid derivatives where R-R6, X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, "endothelin" or "ET" signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, (1988) 411-415; FEBS Letters, 231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988) 868-875).

Increased or abnormal release of endothelin causes persistent vasoconstruction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that elevated plasma levels of endothelin were found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, (1989) 79, J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868).

Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.

We have found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.

The invention relates to carboxylic acid derivatives of the formula I ##STR2## where R is formyl, tetrazole sic!, nitrile sic!, a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R² hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio;

X nitrogen or CR¹⁴ where R¹⁴ is hydrogen or C₁₋₅ -alkyl, or CR¹⁴ forms together with CR³ a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C₁₋₄ -alkyl groups and in which in each case a methylene group can be replaced by oxygen, sulfur, --NH or --NC₁₋₄ -alkyl;

R³ hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -Alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, --NH--O--C₁₋₄ -alkyl, C₁ -C₄ -alkylthio or CR³ is linked to CR¹⁴ as indicated above to give a 5- or 6-membered ring;

R⁴ and R⁵ (which can be identical or different):

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; or

phenyl or naphthyl, which are connected together in the ortho positions via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂ -, NH- or N-alkyl group, or C₃ -C₇ -cycloalkyl;

R⁶ hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl, C₃₋₈ -alkylcarbonylalkyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, phenyl or phenyl or phenoxy which is substituted one or more times, eg. one to three times, by halogen, mitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, dioxomethylene sic! or dioxoethylene sic!;

a five- or six-membered heteroaromatic moiety containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio;

with the proviso that R⁶ can be hydrogen only when Z is not a single bond;

Y sulfur or oxygen or a single bond;

Z sulfur or oxygen or a single bond.

The compounds, and the intermediates for preparing them, such as IV and VI, may have one or more asymmetrical substituted carbon atoms. Such compounds may be in the form of the pure enantiomers or pure diastereomers or a mixture thereof. The use of an enantiomerically pure compound as active substance is preferred.

The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing endothelin receptor inhibitors.

The invention furthermore relates to the preparation of the compounds of the formula IV in enantiomerically pure form. Enantioselective epoxidation of an olefin with two phenyl substituents is known (J. Org. Chem. 59, 1994, 4378-4380). We have now found, surprisingly, that even ester groups in these systems permit epoxidation in high optical purity.

The preparation of the compounds according to the invention where Z is sulfur or oxygen starts from the epoxides IV, which are obtained in a conventional manner, eg. as described in J. March, Advanced Organic Chemistry, 2nd ed., 1983, page 862 and page 750, from the ketones II or the olefins III: ##STR3##

Carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (eg. with R═ROOR¹⁰ sic!) with alcohols or thiols of the general formula V where R⁶ and Z have the meanings stated in claim 1. ##STR4##

To do this, compounds of the general formula IV are heated with compounds of the formula V, in the molar ratio of about 1:1 to 1:7, preferably 1 to 3 mole equivalents, to 50-200° C., preferably 80-150° C.

The reaction can also take place in the presence of a diluent. All solvents which are inert toward the reagents used can be used for this purpose.

Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, alcohols, such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, bases such as pyridine, cyclic ureas such as 1,3-dimethylimidazolidin-2-one and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

The reaction is preferably carried out at a temperature in the range from 0° C. to the boiling point of the solvent or mixture of solvents.

The presence of a catalyst may be advantageous. Suitable catalysts are strong organic and inorganic acids, and Lewis acids. Examples thereof are, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV) alcoholates.

Compounds of the formula VI where R⁴ and R⁵ are cycloalkyl can also be prepared by subjecting compounds of the formula VI where R⁴ and R⁵ are phenyl, naphthyl, or phenyl or naphthyl substituted as described above, to a nuclear hydrogenation.

Compounds of the formula VI can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula IV and reacting them in the manner described with compounds of the formula V.

It is furthermore possible to obtain enantiomerically pure compounds of the formula VI by carrying out a classical racemate resolution on racemic or diastereomeric compounds of the formula VI using suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine sic!, chinchonine sic!, yohimbine, morphine, dehydroabietylamine, ephedrine (-), (+), deoxyephedrine (+), (-), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (-), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (-) threo-2-amino-1-phenyl-1,3-propanediol (+), (-), α-methylbenzylamine (+), (-), α-(1-naphthyl)ethylamine (+), (-), α-(2-naphthyl)ethylamine (+), (-), aminomethylpinane, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives, peptide derivatives.

The compounds according to the invention where Y is oxygen, and the remaining substituents have the meanings stated under the general formula I, can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula VI where the substituents have the stated meanings with compounds of the general formula VII ##STR5## where R¹⁵ is halogen or R¹⁶ --SO₂ --, where R¹⁶ can be C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl or phenyl. The reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. of a base which deprotonates the intermediate VI, in a temperature range from room temperature to the boiling point of the solvent.

Compounds of the formula VII are known, some of them can be bought, or they can be prepared in a generally known manner.

It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide.

The compounds according to the invention where Y is sulfur, and the remaining substituents have the meanings stated under the general formula I, can be prepared, for example, by reacting carboxylic acid derivatives of the general formula VIII, which can be obtained in a known manner from compounds of the general formula VI and in which the substituents have the abovementioned meanings, with compounds of the general formula IX, where R², R³ and X have the meanings stated under general formula I. ##STR6##

The reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. a base which deprotonates the intermediate IX, in a temperature range from room temperature to the boiling point of the solvent.

It is possible to use as base, besides those mentioned above, organic bases such as triethylamine, pyridine, imidazole or diazabicycloundecane sic!.

Carboxylic acid derivatives of the formula VIa (z in formula VI=direct linkage) can be prepared by reacting epoxides of the formula IV with cuprates of the formula XI: ##STR7##

The cuprates can be prepared as described in Tetrahedron Letters 23, (1982) 3755.

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R is COOH, and initially converting these in a conventional manner into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxy compound HOR¹⁰. This reaction can be carried out in the usual solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxy compound in the presence of a dehydrating agent such as a carbodiimide.

In addition, it is also possible for compounds of the formula I to be prepared by starting from the salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R is COR¹ and R¹ is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R¹ -A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R¹ -A with a reactive substituent A are known or can be easily obtained with general expert knowledge. This reaction can be carried out in conventional solvents and advantageously takes place with the addition of a base, in which case those mentioned above are suitable.

The radical R in formula I may vary widely. For example, R is a group ##STR8## where R¹ has the following meanings: a) hydrogen;

b) succinylimidoxy sic!;

c) a five-membered heteroaromatic moiety linked by a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, in particular fluorine and chlorine and/or one or two of the following radicals:

C₁ -C₄ -alkyl such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;

C₁ -C₄ -haloalkyl, in particular C₁ -C₂ -haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;

C₁ -C₄ -haloalkoxy, in particular C₁ -C₂ -haloalkoxy such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, in particular trifluoromethoxy;

C₁ -C₄ -alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy;

C₁ -C₄ -alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, in particular methylthio and ethylthio;

d) R¹ furthermore a radical ##STR9## where m is 0 or 1 and R⁷ and R⁸, which can be identical or different, have the following meanings:

hydrogen

C₁ -C₈ -alkyl, in particular C₁ -C₄ -alkyl as mentioned above;

C₃ -C₆ -alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl;

C₃ -C₆ -alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, in particular 2-propynyl

C₃ -C₈ -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, where these alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry one to five halogen atoms, in particular fluorine or chlorine and/or one or two of the following groups:

C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy as mentioned above, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkenylthio, C₃ -C₆ -alkynyloxy, C₃ -C₆ -alkynylthio, where the alkenyl and alkynyl constituents present in these radicals preferably have the abovementioned meanings;

C₁ -C₄ -alkylcarbonyl such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl;

C₁ -C₄ -alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl;

C₃ -C₆ -alkenylcarbonyl, C₃ -C₆ -alkynylcarbonyl, C₃ -C₆ -alkenyloxycarbonyl and C₃ -C₆ -alkynyloxycarbonyl, where the alkenyl and alkynyl radicals are preferably defined as detailed above;

phenyl, unsubstituted or substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl;

di-C₁ -C₄ -alkylamino such as, in particular, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropyl-N-ethylamino, N-isopropyl-N-propylamino;

R⁷ and R8 furthermore phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, as mentioned above in particular;

or R⁷ and R⁸ together form a C₄ -C₇ -alkylene chain which is closed to form a ring, is unsubstituted or substituted, eg. substituted by C₁ -C₄ -alkyl, and may contain a heteroatom selected from the group consisting of oxygen, sulfur or nitrogen, such as --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₆ --, --(CH₂)₇ --, --(CH₂)₂ --O--(CH₂)₂ --, --CH₂ --S--(CH₂)₃ --, --(CH₂)₂ --O--(CH₂)₃ --, --NH--(CH₂)₃ --, --CH₂ --NH--(CH₂)₂ --, --CH₂ --CH═CH--CH₂ --, --CH═CH--(CH₂)--₃ --;

e) R¹ furthermore a group ##STR10## where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R⁹ is C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or unsubstituted or substituted phenyl, as mentioned above in particular.

f) R¹ furthermore a radical OR¹⁰, where R¹⁰ is:

hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium or an environmentally compatible organic ammonium ion such as tertiary C₁ -C₄ -alkylammonium or the ammonium ion;

C₃ -C₈ -cycloalkyl as mentioned above, which may carry one to three C₁ -C₄ -alkyl groups;

C₁ -C₈ -alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, which can carry one to five halogen atoms, in particular fluorine and chlorine and/or one of the following radicals:

C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, cyano, C₁ -C₄ -alkylcarbonyl, C₃ -C₈ -cycloalkyl, C₁ -C₄ -alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aromatic radicals in turn can carry in each case one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned above in particular;

a C₁ -C₈ -alkyl as mentioned above, which can carry one to five halogen atoms, in particular fluorine and/or chlorine, and carries one of the following radicals: a 5-membered heteroaromatic moiety containing one to three nitrogen atoms, or a 5-membered heteroaromatic moiety containing a nitrogen atom and an oxygen or sulfur atom, which can carry one to four halogen atoms and/or one or two of the following radicals:

nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl;

a C₂ -C₆ -alkyl group which carries one of the following radicals in position 2: C₁ -C₄ -alkoxyimino, C₃ -C₆ -alkynyloxyimino, C₃ -C₆ -haloalkenyloxyimino or benzyloxyimino;

a C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;

R¹⁰ furthermore a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned above in particular;

a 5-membered heteroaromatic moiety which is linked via a nitrogen atom, contains one to three nitrogen atoms and can carry one or two halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;

R¹⁰ furthermore a group ##STR11## where R¹¹ and R¹², which can be identical or different, are: C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or an unsubstituted or substituted phenyl radical, as mentioned above in particular;

phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, where these radicals are, in particular, those mentioned above;

or R¹¹ and R¹² together form a C₃ -C₁₂ -alkylene chain which can carry one to three C₁ -C₄ -alkyl groups and contain a heteroatom from the group consisting of oxygen, sulfur and nitrogen, as mentioned in particular for R⁷ and R⁸.

g) R¹ furthermore a radical ##STR12## where R¹³ is: C₁ -C₄ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl as mentioned above in particular, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or a phenyl radical as mentioned above;

phenyl, unsubstituted or substituted, in particular as mentioned above.

h) R¹ a radical ##STR13## where R¹³ has the abovementioned meaning. R can furthermore be:

tetrazole sic! or nitrile sic!.

In respect of the biological effect, preferred carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:

R² hydrogen, hydroxyl, N(C₁ -C₄ -alkyl)₂, the C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio groups and halogen atoms mentioned in detail for R¹, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

X nitrogen or CR¹⁴ where

R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4- to 5-membered alkylene or alkenylene ring in which, in each case, a methylene group can be replaced by oxygen or sulfur, such as --CH₂ --CH₂ --O--, --CH═CH--O--, --CH₂ --CH₂ --CH₂ --O--, --CH═CH--CH₂ O--, in particular hydrogen, --CH₂ --CH₂ --O--, --CH(CH₃)--CH(CH₃)--O--, --C(CH₃)═C(CH₃)--O--, --CH═C(CH₃)--O-- or --C(CH₃)═C(CH₃)--S;

R³ the hydrogen, hydroxyl, N(C₁ -C₄ -alkyl)₂, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio groups and halogen atoms mentioned for R¹, especially chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or is linked to R¹⁴ as mentioned above to give a 5- or 6-membered ring;

R⁴ and R⁵ phenyl or naphthyl, which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl; phenyl or naphthyl, which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group, or C₃ -C₇ -cycloalkyl;

R⁶ C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl as mentioned above in particular, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, hydroxycarbonyl, C₁ -C₄ -alkoxycarbonyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino or unsubstituted or substituted phenyl or phenoxy, as mentioned above in particular;

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -akylamino sic! or C₁ -C₄ -dialkylamino, as mentioned in particular for R⁷ and R⁴ ;

a five- or six-membered heteroaromatic moiety which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned for R⁴ in particular;

Y sulfur, oxygen or a single bond;

Z sulfur, oxygen, --SO--, --SO₂ --or a single bond.

Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:

R² C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy

X nitrogen or CR¹⁴, where

R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4- or 5-membered alkylene or alkenylene ring such as --CH₂ --CH₂ --CH₂ --, --CH═CH--CH₂ --, in which in each case a methylene group can be replaced by oxygen or sulfur, such as --CH₂ --CH₂ --O--, --CH═CH--O--, --CH₂ --CH₂ --CH₂ --O--, --CH═CH--CH₂ O--, in particular hydrogen, --CH₂ --CH₂ --O--, --CH(CH₃)--CH(CH₃)--O--, --C(CH₃)═C(CH₃)--O--, --CH═C(CH₃)--O-- or --C(CH₃)═C(CH₃)--S;

R³ the C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio groups mentioned for R¹, or is linked to R¹⁴ as mentioned above to give a 5- or 6-membered ring;

R⁴ and R⁵ phenyl (identical or different) which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio or

R⁴ and R⁵ are phenyl groups which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group; or

R⁴ and R⁵ are C₃ -C₇ -cycloalkyl;

R⁶ C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl or C₃ -C₈ -cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₁ -C₄ -alkylthio;

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -akylamino sic! or C₁ -C₄ -dialkylamino;

a five- or six-membered heteroaromatic moiety which contains a nitrogen atom and/or a sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy and/or C₁ -C₄ -alkylthio; Y sulfur, oxygen or a single bond;

Z sulfur, oxygen, --SO--, --SO₂ -- or a single bond.

The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, or hypertension or kidney failure caused by ischemia or intoxication.

The good effect of the compounds can be shown in the following tests:

Receptor binding studies

Cloned human ET_(A) receptor-expressing CHO cells and guinea pig cerebellar membranes with >60% ET_(B) compared with ET_(A) receptors were used for binding studies.

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA).

After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization was then carried out with F₁₂ medium, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4° C. for 30 min. The membranes were centrifuged at 20,000×g for 10 min, and the pellet was stored in liquid nitrogen.

Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and lacuna! obtained by differential centrifugation at 1000×g for 10 min and repeated centrifugation of the supernatant at 20,000×g for 10 min.

Binding assays

For the ET_(A) and ET_(B) receptor binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl₂, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture and incubated with 25 pM 125I!-ET₁ (ET_(A) receptor assay) or 25 pM 125I!-RZ₃ (ET_(B) receptor assay) in the presence and absence of test substance at 25° C. The nonspecific binding was determined using 10⁻⁻⁷ M ET₁. After 30 min, the free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional in vitro assay system to look for endothelin receptor (subtype A) antagonists

This assay system is a functional, cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.

1-Fibroblasts which had been isolated from rats and in which an endogenous endothelin receptor of the A subtype had been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2×10⁶ /ml and incubated with Fura 2-am (2 μM), Pluronics F-127 (0.04%) und DMSO (0.2%) at 37° C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2×10⁶ /ml.

The fluorescence signal from 2×10⁵ cells per ml with Ex/Em 380/510 was recorded continuously at 30° C. The test substances and, after an incubation time of 3 min, ET1 lacuna! to the cells, the maximum change in the fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance was used as control and was set equal to 100%.

Testing of ET antagonists in vivo

Male SD rats weighting 250-300 g were anesthetized with amobarbital, artifically ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized sic!.

In control animals, intravenous administration of 1 μg/kg ET1 led to a distinct rise in blood pressure which persisted for a lengthy period.

The test animals received an i.v. injection of the test compounds (1 ml/kg) 5 min before the administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.

Endothelin-1-induced sudden death in mice

The principle of the test is the inhibition of the sudden heart death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight results in death of the animals within a few minutes.

The lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, the endothelin-1 injection which was lethal in the reference group usually takes place 5 min thereafter. With other modes of administration, the times before administration are extended, where appropriate up to several hours.

The survival rate is recorded, and effective doses which protect 50% of the animals (ED 50) from endothelin-induced heart death for 24 h or longer are determined.

Functional test on vessels for endothelin receptor antagonists

Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and pH 7.3-7.4, first induced to contract with K⁺. After washing out, an endothelin dose-effect plot up to the maximum is constructed.

Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calibrated as a % of the K⁺ -induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active substance is, as a rule, about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellent gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of the active substance.

SYNTHESIS EXAMPLES Example 1

Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of absolute methanol and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was distilled out, the residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation there remained 5.5 g (88%) of a pale yellow oil.

Example 2

Methyl 2-hydroxy-3-phenoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60 mmol) of phenol were heated together at 100° C. for 6 h. Removal of the excess phenol by distillation under high vacuum and purification of the residue by chromatography on silica gel with hexane/ethyl acetate mixtures resulted in 4.9 g (77%) of a pale yellow oil.

Example 3

Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate

2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained.

Melting point 81° C.

Example 4

2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained.

Melting point 167° C.

Example 5

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl sodium sic! propionate

1.68 g (4 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic acid are dissolved in 4 ml of 1N NaOH+100 ml of water. The solution is freeze-dried, and the sodium salt of the carboxylic acid used is obtained quantitatively.

10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml each of methanol and glacial acetic acid, 1 ml of RuO(OH)₂ in dioxane was added, and hydrogenation was carried out with H₂ in an autoclave at 100° C. under 100 bar for 30 h. The catalyst was filtered off, the mixture was concentrated, mixed with ether and washed with NaCl solution, and the organic phase was dried and concentrated. 10.1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate were obtained as an oil.

Example 7

Methyl 2- (4,6-dimethoxy-pyrimidin-2-yl)thio!-3-methoxy-3, 3-diphenylpropionate sic!

7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine were added, and 3.2 g (28 mmol) of methanesulfonyl chloride were added dropwise while stirring. The mixture was stirred at room temperature for 2 h, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of DMF. After stirring at room temperature for 2 h and at 60° C. for a further 2 h, the mixture was poured into 1 liter of ice-water, and the resulting precipitate was filtered off with suction. After drying, 3.19 g (29%) of a white powder remained.

Example 8

Methyl 2-hydroxy-3,3-diphenylbutyrate

1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in 10 ml of absolute ether were added dropwise to a cup-rate solution which had been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normal methyllithium solution and had been cooled to -78° C. The solution was stirred at -78° C. for 1 h and then allowed to warm to room temperature. It was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with sodium bicarbonate solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a pale yellow oil.

Example 9

2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodium methoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) at room temperature. After cooling to -100° C., 92.24 g (0.85 mol) of methyl chloroacetate were added in such a way that the internal temperature rose to 40° C. while continuing to cool in a bath at -10° C. The mixture was then stirred without cooling at the autogenous temperature for one hour. After addition of 250 ml of water and brief stirring, the aqueous phase was separated off. The MTB phase was washed with 250 ml of dilute sodium chloride solution. After the solvent had been changed to methanol (250 ml), a solution of 1 g of p-toluenesulfonic acid in 10 ml of methanol was added at room temperature. The mixture was stirred at autogenous temperature for one hour and then heated to reflux. While distilling out the methanol, 400 g of a 10% strength sodium hydroxide solution was added dropwise, and finally 60 ml of water were added. The methanol was distilled out until the bottom temperature reached 97° C. After cooling to 55° C., 190 ml of MTB were added and the mixture was acidified to pH 2 with about 77 ml of concentrated HCl. After cooling to room temperature, the aqueous phase was separated off and the organic phase was concentrated by distilling out 60 ml of MtB sic!. The product was crystallized by adding 500 ml of heptane and slowly cooling to room temperature. The coarsely crystalline solid was filtered off with suction, washed with heptane and dried to constant weight in a vacuum oven at 40° C.

Yield: 108.9 g (80%), HPLC >99.5% area.

Example 10

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with L-proline methyl ester)

148.8 g of a 30% strength methanolic sodium methanolate solution (0.826 mol) were added dropwise to 240 g of a 57% strength methanolic L-proline methyl ester hydrochloride solution (0.826 mol) at room temperature, and 2.4 l of MTB and 225 g (0.826 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After 2680 ml of MTB/methanol mixture had been distilled out with simultaneous dropwise addition of 2.4 l of MTB, the mixture was slowly cooled to room temperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x L-proline methyl ester) were filtered off with suction, and the solid was washed with 150 ml of MTB. The filtrate was concentrated by distilling out 1.5 l of MTB, and 1.0 l of water was added. The pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature and, after stirring and phase separation, the aqueous phase was separated off and extracted with 0.4 l of MTB. The combined organic phases were extracted with 0.4 l of water. The residue after the MTB had been stripped off was dissolved in 650 ml of toluene under reflux, and the product was crystallized by seeding and slow cooling. Filtration with suction, washing with toluene and drying in a vacuum oven resulted in 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate).

Chiral HPLC: 100% pure; HPLC: 99.8%

Example 11

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with (S)-1-(4-nitrophenyl)ethylamine)

30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100 g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750 ml of acetone and 750 ml of MTB under reflux, the mixture was seeded, boiled under reflux for one hour and slowly cooled to room temperature for crystallization. The crystals (S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x (S)-1-(4-nitrophenyl)ethylamine) were filtered off with suction and washed with MTB. The residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated off and extracted with 150 ml of MTB. The combined organic phases were extracted with 100 ml of water. 370 ml of MTB were distilled out and then 390 ml of n-heptane were added under reflux, and the mixture was slowly cooled to room temperature while the product crystallized. Filtration with suction, washing with n-heptane and drying in a vacuum oven resulted in 35.0 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate).

Chiral HPLC: 100% pure; HPLC: 99.8%

Example 12

Benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate

24.48 g (90 mmol) of 3-methoxy-3,3-diphenyl-2-hydroxypropionic acid were dissolved in 150 ml of DMF, and 13.7 g (99 mmol) of potassium carbonate were added. The suspension was stirred at room temperature for 30 min. Then 10.7 ml (90 mmol) of benzyl bromide were added dropwise over the course of 5 min, and the mixture was stirred for 1 h, during which the temperature rose to 32° C.

To this mixture were successively added 24.84 g (180 mmol) of K₂ CO₃ and 20.52 g (90 mmol) of 2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentapyridine sic!, and the mixture was stirred at 80° C. for 3 h.

For workup, the contents of the flask were diluted with about 600 ml of H₂ 0 and cautiously acidified with concentrated HCl, and 250 ml of ethyl acetate were added. 31.4 g of pure product precipitated and were filtered off.

The ethyl acetate phase was separated from the mother liquor, the aqueous phase was extracted again with ethyl acetate, and the combined organic phases were concentrated. The oily residue (19 g) was purified by chromatography (cyclohexane/ethyl acetate=9/1) to result in a further 10.5 g of pure product.

Total yield: 41.9 g (82.2 mmol)=91%; Melting point 143-147° C.; MS: MH⁺ =511

Example 13

3-Methoxy-2-(4-methoxy-(6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3,3-diphenylpropionic sic! acid

40 g (78.4 mmol) of benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate were dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mg of palladium on active carbon (10%) were added, and the mixture was exposed to a hydrogen atmosphere until no further gas was taken up. The catalyst was filtered off, the solution was evaporated, and the residue was crystallized from ether.

Example 14

Ethyl 2S-3,3-diphenyloxirane-2-carboxylate

2.57 g (10.2 mnol) of ethyl 3,3-diphenylacrylate and 464 mg of 4-phenylpyridine N-oxide were dissolved in 24 ml of methylene chloride, and 432 mg (6.5 mol %) of (5,5)-(+)-N,N'-bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride were added. While cooling in ice, 6.4 ml of a 12% strength sodium hypochloride sic! solution were added, and the mixture was stirred while cooling in ice for 30 min and at room temperature overnight. The solution was diluted to 200 ml with water, extracted with ether, dried and evaporated. 2.85 g of a colorless oil were obtained. Purification by NPLC sic! (cyclohexane:ethyl acetate=9:1) resulted in 1.12 g of oil with an enantiomer ratio of about 8:1 in favor of the S configuration.

¹ H-NMR CDCl₃ !, δ=1.0 (t, 3H); 3.9 (m, 3H); 7.3 (m, 10H)

Example 15

2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol sic!

46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g (192 mmol) of 5-methylisothiourea sic! sulfate were successively added to 29.6 g (528 mmol) of KOH in 396 ml of methanol, and the mixture was stirred at room temperature overnight, acidified with 1N hydrochloric acid and diluted with water. The crystals which separated out were filtered off with suction and dried. 20 g of crystals were obtained.

Example 16

sulfanyl 4-Chloro-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine sic!

255 ml of phosphorus oxychloride were added to 20 g (110 mmol) lacuna!, and the mixture was stirred at 80 ° C. for 3 hours. Phosphorus oxychloride was evaporated off, ice was added to the residue, and the crystals which separated out were filtered off with suction. 18.5 g of a brownish solid were obtained.

Example 17

4-Methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine sic!

18.05 g (90 mmol) of 4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine sic! were dissolved in 200 ml of methanol. At 45 ° C., 16.7 g of sodium methoxide (as 30% strength solutions sic! in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.

¹ H-NMR DMSO!, δ=2.1 (quintet, 2H); 2.5 (s, 3H); 2.8 (dt, 4H); 3.9 (s, 3H) ppm

Example 18

2-Methylsulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentopyrimidine sic!

15 g (76.2 mmol) of 4-methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine sic! were dissolved in 160 ml of glacial acetic acid/methylene chloride (1:1), and 1.3 g of sodium tungstate were added. At 35° C., 17.5 ml (170 ml sic!) of a 30% strength H₂ O₂ solution were added dropwise. The mixture was then diluted with 500 ml of water and 100 ml of methylene chloride, and the organic phase was separated off, dried and evaporated. 14 g of oil remained and were crystallized from ether.

¹ H-NMR CDCl₃ !, δ=2.2 (quintet, 2H); 3.0 (dt., 4H); 3.3 (s, 3H); 4.1 (s, 3H) ppm

Example 19

1-Benzenesulfonyl-3-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxy-4,4-diphenyl-2-butanone

0.37 g (2.4 mmol) of phenyl methane sic! sulfone were dissolved in 10 ml of dry THF and then, at -70° C., 2 eq. of butyllithium (2.94 ml; 1.6 molar solution in hexane) were added dropwise. After 1 h at -70° C., 1 g (2.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropynoate sic! dissolved in 5 ml of THF was added dropwise. The reaction mixture was then stirred at -70° C. for 1 h and at -10° C. for 1 h and then warmed to room temperature. For workup, about 10 ml of saturated NH₄ Cl solution were added dropwise, thorough extraction with ethyl acetate was carried out, and the combined organic phases lacuna! with-saturated N-Cl sic! solution and dried over Na₂ SO₄. The residue obtained after drying and concentration was purified by chromatography on silica gel (n-heptane/ethyl acetate 15%→30%) and subsequently MPLC on RP silica gel (acetonitrile/H₂ O+TFA); 0.3 g of a white amorphous powder was obtained as product.

Example 20

3,3-Diphenyloxiram-2-carbonitrile sic!

3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of dry THF and then, at -10° C., a mixture of 5 g (27.4 mmol) of benzophenone and 4.2 g (54.9 mmol) of chloroacetonitrile was added dropwise.

The reaction mixture was stirred at -10° C. for about 2 h, then poured into water and extracted several times with ethyl acetate. The combined organic phases were dried over Na₂ SO₄ and concentrated, and the residue was purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 1.2 g (20%)

¹ H-NMR CDCl₃ !, δ=3.9 (s, 1H); 7.4-7.5 (m, 10 H) ppm

Example 21

2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile

6.5 lacuna! (29.4 mmol) of 3,3-diphenyloxirane-2-carbonitrile were dissolved in 60 ml of methanol and, at 0° C., about 2 ml of boron trifluoride etherate solution were added. The mixture was stirred further at 0° C. for 1 h and then at room temperature overnight. For workup it was diluted with diethyl ether and washed with saturated NaCl solution, and the organic phase was dried over Na₂ SO₄ and concentrated. The residue comprised 7.3 g of a white amorphous powder which was used directly in the subsequent reactions.

¹ H-NMR CDC₁₃ !, δ=2.95 (broad s, OH), 3.15 (s, 3H), 5.3 (s, 1H), 7.3-7.5 (m, 10) ppm

Example 22

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionitrile

7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K₂ CO₃ and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H₂ O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-hepane/ethyl acetate).

Yield: 6.9 g of white amorphous powder

FAB-MS: 392 (M+H⁺) ¹ H-NMR CDCl₃ !, δ=3.3 (s, 3H); 4.95 (s, 6H), 5.85 (s, 1H); 6.3 (s, 1H); 7.3-7.5 (m, 10H) ppm

Example 23

5- 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl!-1H-tetrazole sic!

0.5 g (1.3 mmol) of nitrile was dissolved in 10 ml of toluene, and 85 mg (1.3 mmol) of NaN₃ and 460 mg (1.4 mmol) of Bu₃ SnCl were successively added, and then the mixture was refluxed for about 40 h. Cooling was followed by dilution with ethyl acetate and washing with 10% aqueous KF solution and with NaCl solution. After drying over MgSO₄ and concentration there remained 1.0 g of a yellow oil, which was purified by chromatography on silica gel (n-heptane/ethyl acetate).

Concentration of the fractions resulted in 60 mg of the 1H-tetrazole and 110 mg of the 1-methyltetrazole, each as amorphous white solids.

5- 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl!-lH-tetrazole sic!

Electrospray-MS: 435 (M+H⁺) ¹ H-NMR (CDCl₃): δ (ppm) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, 1H), 7.25-7.40 (m, 10H), 7.50 (s, 1H).

5- 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl!-1-methyltetrazole sic!

Electrospray-MS; 471 (M+H⁺) ¹ H-NMR (CDCl₃): δ (ppm) 3.0 (s, 3H), 3.35 (s, 3H9 sic!, 3.80 (s, 6H), 5.75 (s, 1H), 7.30-7.40 (m, 11H).

Example 24

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfinyl-3,3-diphenylpropionic acid

1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic sic! acid were introduced into 15 ml of glacial acetic acid at 0° C. and 294 μl of 30% strength H₂ 0₂ were added dropwise. The mixture was stirred at room temperature overnight, poured into water, extracted with CH₂ Cl₂ and washed with sodium thiosulfate solution and brine. After drying, 1 g of substance was isolated as a white foam.

Example 25

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic acid

0.6 g (1.45 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methyl-sulfonyl-3,3-diphenylpropionic sic! acid was introduced into 15 ml of glacial acetic acid at room temperature, and 294 μl of 30% strength H₂ 0₂ were added dropwise. The mixture was stirred at room temperature overnight, heated at 50° C. for a further 3 h, poured into water and washed with sodium thiosulfate solution and brine. After drying, 400 mg were isolated as a white solid.

The compounds listed in Table 1 sic! can be prepared in a similar way.

    TABLE I       -       ##STR14##      1       No. R.sup.1 R.sup.4, R.sup.5 R.sup.6 R.sup.2 R.sup.3 X Y Z m.p. °       C.!       I-195 OMe Phenyl Methyl OMe OMe CH O O 81       I-196 OH Phenyl Methyl OMe OMe CH O O 167       I-197 OH Phenyl CH.sub.2 --CH.sub.2 --S--CH.sub.3 OMe OMe CH O O              I-198 OH Phenyl Ethyl OMe OMe CH O O 81(decomp.)       I-199 OH Phenyl iso-Propyl OMe OMe CH O O 182       I-200 OH Phenyl Methyl OMe OMe CH O S 168       I-201 OH Phenyl CH.sub.2 --CH.sub.2 --SO.sub.2 --CH(CH.sub.3).sub.2 OMe      OMe CH O O       I-202 OH Phenyl CH.sub.2 --CH.sub.2 --SO.sub.2 --CH(CH.sub.3).sub.2 OMe      OMe CH S O       I-203 OH Phenyl CH.sub.2 --CH.sub.2 --SO.sub.2 --CH(CH.sub.3).sub.2 OMe      OMe C--CH(CH.sub.3).sub.2 O O       I-204 OH Phenyl CH.sub.2 --CH.sub.2 --SO.sub.2 --CH(CH.sub.3).sub.2 OMe      OMe C--CH(CH.sub.3).sub.3 O O       I-205 OH Phenyl CH.sub.2 --CH.sub.2 --SO.sub.2 --CH(CH.sub.3).sub.2 OMe      NH--OCH.sub.3 CH O O       I-206 OH Phenyl n-Propyl OMe OMe CH O O 174       I-207 OMe Phenyl n-Propyl OMe OMe CH O O       I-208 OH Phenyl n-Propyl OEt OEt CH O O       I-209 OH Phenyl n-Butyl OMe OMe CH O O       I-210 OH Phenyl iso-Butyl OMe OMe CH O O       I-211 OH Phenyl iso-Butyl OMe O--CH.sub.2 --CH.sub.2       --C O O             I-212 OH Phenyl tert.-Butyl OMe OMe CH O O               I-213 OH Phenyl Cyclopropyl OMe OMe CH O O       I-214 OH Phenyl Cyclopentyl OMe OMe CH O O       I-215 OH Phenyl Cyclohexyl OMe OMe CH O O       I-216 OH Phenyl (CH.sub.3).sub.3 C--CH.sub.2 --CH.sub.2 OEt OEt CH O O        I-217 OH Phenyl (CH.sub.3).sub.2 CH--CH.sub.2 --CH.sub.2 --CH.sub.2      OMe OMe CH O O 173       I-218 OH Phenyl HO--CH.sub.2       --CH.sub.2 OMe OMe CH O O                   I-219 OH Phenyl HO.sub.2      C--(CH.sub.2).sub.2       -- OMe OMe CH O O                                     I-220 OH Phenyl      Cyclopropylmethylene sic! OMe OMe CH O O 115       I-221 OH Phenyl H OMe OMe CH O O       I-222 OH Phenyl Methyl OMe OMe CH O --       I-223 OH Phenyl Phenyl OMe OMe CH O O 136       I-224 OH Phenyl Phenyl OMe O--CH(CH.sub.3)--CH.sub.2       --C O O             I-225 OH Phenyl Phenyl OMe OMe CH O O       I-226 OH Phenyl 4-Isopropyl-Phenyl OMe OMe CH O O       I-227 OH Phenyl 4-Me-S-Phenyl OMe OMe CH O O       I-228 OH Phenyl 4-Me-O-Phenyl OMe OMe CH O O       I-229 OH Phenyl 3-Et-Phenyl OMe OMe CH O O       I-230 OH Phenyl 2-Me-Phenyl OMe OMe CH O O       I-231 OH Phenyl 2-Cl-Phenyl OMe OMe CH O O       I-232 OH Phenyl 3-Br-Phenyl OMe OMe CH O O       I-233 OH Phenyl 4-F-Phenyl OMe OMe CH O O       I-234 OH Phenyl 4-F-Phenyl OMe OMe CH S O       I-235 OH Phenyl 4-CH.sub.3       -Phenyl OMe OMe CH O O                        I-236 OH Phenyl 3-NO.sub.2       -Phenyl OMe OMe CH O O       I-237 OH Phenyl 2-HO-Phenyl OMe OMe CH O O       I-238 OH Phenyl 3,4-Dimethoxyphenyl OMe OMe CH O O       I-239 OH Phenyl 3,4-Dioxomethylenephenyl OMe OMe CH O O           sic!       I-240 OH Phenyl 3,4,5-Trimethoxyphenyl OMe OMe CH O O       I-241 OH Phenyl Benzyl OMe OMe CH O O       I-242 OH Phenyl 2-Cl-Benzyl OMe OMe CH O O       I-243 OH Phenyl 3-Br-Benzyl OMe OMe CH O O       I-244 OH Phenyl 4-F-Benzyl OMe OMe CH O O       I-245 OH Phenyl 2-Me-Benzyl OMe OMe CH O O       I-246 OH Phenyl 2-Me-Benzyl OMe O--CH═CH--C O O       I-247 OH Phenyl 3-Et-Benzyl OMe OMe CH O O       I-248 OH Phenyl 4-iso-Propyl-Benzyl OMe OMe CH O O       I-249 OH Phenyl 4-NO.sub.2       -Propyl-Benzyl OMe OMe CH O O                 I-250 OH Phenyl 2-Me-5-Pro      pyl-Benzyl OMe OMe CH O O       I-251 OH Phenyl 2-Me-5-Propyl-Benzyl OEt OEt CH O O       I-252 OH Phenyl 4-Me-2-Propyl-Benzyl OMe OMe CH O O       I-253 OH Phenyl 3,4-Dioxomethylenebenzyl OMe OMe CH O O           sic!       I-254 OH 4-F-Phenyl Methyl OMe OMe CH O O 163-165                (decomp.)       I-255 OMe 4-F-Phenyl Methyl OEt OEt CH O O       I-256 OH 4-Cl-Phenyl Methyl OMe OMe CH O O       I-257 OH 4-Me-O-Phenyl Methyl OMe OMe CH O O       I-258 OH 4-Me-O-Phenyl Ethyl OMe OMe CH O O       I-259 OH 4-Me-Phenyl Methyl OMe OMe CH O O       I-260 OH 4-Me-Phenyl Methyl OMe O--CH.sub.2 --CH.sub.2       --C O O           I-261 OH 3-CF.sub.3 -Phenyl n-Propyl OMe OMe CH O O         I-262 OH 3-CF.sub.3 -Phenyl n-Propyl OMe O--CH(CH.sub.3)--CH.sub.2      --C O O       I-263 OH 4-NO.sub.2       -Phenyl Methyl OMe OMe CH O O                        I-264 OH 4-NO.sub.2       -Phenyl Methyl OMe O--CH═CH--C O O       I-265 OH 3-Cl-Phenyl Ethyl OMe OMe CH O O       I-266 OH 2-F-Phenyl Methyl OMe OMe CH O O 193-194                (decomp.)       I-267 OH 2-F-Phenyl Methyl OMe OMe CH S O       I-268 OH 2-Me-O-Phenyl Methyl OMe OMe CH O O       I-269 OH 2-Me-O-Phenyl Methyl OMe OMe CH O S       I-270 OH 3,4-Dimethoxyphenyl Methyl OMe OMe CH O O       I-271 OH 3,4-Dioxomethylenephenyl Methyl OMe OMe CH O O          sic!       I-272 OH p-CF.sub.3       -Phenyl Methyl OMe OMe CH O O                        I-273 OH Phenyl      Methyl OMe OEt CH O O       I-274 OMe Phenyl Methyl OMe OEt CH S O       I-275 OH Phenyl Ethyl OMe NH--OMe CH O O       I-276 OH p-Me-O-Phenyl n-Propyl OMe OCF.sub.3 CH O O       I-277 OH Phenyl Methyl OMe CF.sub.3 CH O O       I-278 OH Phenyl Methyl OMe CF.sub.3 N O O       I-279 OH 3,4-Dimethoxyphenyl Benzyl Me Me  O O       I-280 OH 3,4-Dimethoxyphenyl Methyl OMe O--CH.sub.2 --CH.sub.2 --C O O       I-281 OH Phenyl Methyl OMe O--CH.sub.2 --CH.sub.2 --C O O 126(decomp.)        I-282 OH Phenyl Methyl OMe O--CH(CH.sub.3)--CH.sub.2       --C O O            I-283 OH Phenyl Methyl OMe N(CH.sub.3)--CH═CH--C      O O 118       I-284 OH Phenyl Methyl OMe S--C(CH.sub.3)═C(CH.sub.3)--C O O              I-285 OH Phenyl Methyl OMe O--C(CH.sub.3)═CH--C O O       I-286 OH Phenyl Methyl Me O--C(CH.sub.3)═CH--C O O       I-287 OH Phenyl Methyl Me O--CH═CH--C O O       I-288 OH 4-F-Phenyl Methyl Me S--CH═CH--C O O       I-289 OH 4-F-Phenyl H OMe OMe CH O O       I-290 OH Phenyl Methyl OMe CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O      149-151               (decomp.)       I-291 OH Phenyl Methyl Methyl CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O      157(decomp.)       I-292 OH Phenyl Methyl Ethyl CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2      --C O O       I-293 OH Phenyl Methyl OMe CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2      --C O O       I-294 OH Phenyl Methyl Me Me CH O O       I-295 OH Phenyl Methyl Et Et CH O O       I-296 OH Phenyl Methyl Me Me C--CH.sub.3 O O       I-297 OH Phenyl Methyl OMe Me CH O O       I-298 OH Cyclohexyl Methyl OMe OMe CH O O       I-299 OH Cyclohexyl Methyl OMe CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O         I-300 OH Phenyl Methyl OCH.sub.3 OCH.sub.3 CH S S       I-301 OH Phenyl Methyl OCH.sub.3 OCH.sub.3 CH O S 134       I-302 OCH.sub.3 Phenyl Methyl OCH.sub.3 OCH.sub.3 CH S S       I-303 OH Phenyl Methyl OCH.sub.3 OCH.sub.3 CH O O       I-304 OCH.sub.3 2-Fluorophenyl Methyl OCH.sub.3 OCH.sub.3 CH O O              I-305 OC.sub.2 H.sub.5 3-Chlorophenyl Methyl OCH.sub.3 OCH.sub.3      N O O       I-306 ON(CH.sub.3).sub.2 4-Bromophenyl Methyl CF.sub.3 CF.sub.3 CH S O        I-307 O--CH.sub.2 --C═CH Phenyl Ethyl OCH.sub.3 CF.sub.3 CH O O          I-308 OH Phenyl Propyl OCH.sub.3 OCF.sub.3 CH O S       I-309 OCH.sub.3 Phenyl i-Propyl OCH.sub.3 CH.sub.3 CH O O       I-310 OC.sub.2       H.sub.5 Phenyl s-Butyl OCH.sub.3 Cl CH S O                I-311      ON(CH.sub.3).sub.2 2-Methylphenyl Methyl OCH.sub.3 OCH.sub.3 CH O O            I-312 ON(CH.sub.3).sub.2 3-Methoxyphenyl Methyl OCH.sub.3 OCH.sub.3       CH O O       I-313 ON═C(CH.sub.3).sub.2 4-Nitrophenyl Methyl OCH.sub.3 OCH.sub.3      CH O O       I-314 ON(CH.sub.3).sub.2 Phenyl 1-Phenylpropyn-3-yl OCH.sub.3 OCF.sub.3      N O S       I-315 ON═C(CH.sub.3).sub.2 2-Hydroxyphenyl Methyl OCH.sub.3      CH.sub.3 N O O       I-316 ONSO.sub.2 C.sub.6 H.sub.5 3-Trifluoromethylphenyl Methyl      OCH.sub.3 Cl N O O       I-317 NHPhenyl 4-Dimethylaminophenyl Methyl OCH.sub.3 OCH.sub.3 CH S O        I-318 OC.sub.2 H.sub.5 Phenyl Trifluoroethyl CH.sub.3 CH.sub.3 CH O O        I-319 ON(CH.sub.3).sub.2 Phenyl Benzyl Cl Cl CH O O       I-320 ON(CH.sub.3).sub.2 Phenyl 2-Methoxyethyl OCH.sub.3 --O--CH.sub.2      --CH.sub.2       -- S O                                                         I-321 OH P      henyl Phenyl OCH.sub.3 OCH.sub.3 CH O O       I-322 OH Phenyl Phenyl OCH.sub.3 --O--CH.sub.2 --CH.sub.2 -- O O              I-323 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 N O O       I-324 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH S O       I-325 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH S S       I-326 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH O S       I-327 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH O O       I-328 OH Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH O O       I-329 OH --(CH.sub.2).sub.5       -- Phenyl Phenyl OCH.sub.3 CH O O            I-330 OH Phenyl 2-Thiozolyl       OCH.sub.3 OCH.sub.3 CH O O       I-331 OCH.sub.3 2-Fluorophenyl Phenyl OCH.sub.3 OCH.sub.3 CH O O              I-332 OC.sub.2 H.sub.5 3-Chlorophenyl Phenyl OCH.sub.3 OCH.sub.3      N O O       I-333 ON(CH.sub.3).sub.2 4-Bromophenyl Phenyl CF.sub.3 CF.sub.3 CH O O        I-334 O--CH.sub.2.tbd. CH Phenyl 2-Fluorophenyl OCH.sub.3 CF.sub.3 CH      O O       I-335 OH Phenyl 3-Chlorophenyl OCH.sub.3 OCF.sub.3 CH O S       I-336 OCH.sub.3 Phenyl 4-Bromophenyl OCH.sub.3 CH.sub.3 CH O O       I-337 OC.sub.2       H.sub.5 Phenyl 4-Thiazolyl OCH.sub.3 Cl CH S O            I-338      ON(CH.sub.3).sub.2 2-Methylphenyl Phenyl OCH.sub.3 OCH.sub.3 CH O O            I-339 ON═C(CH.sub.3).sub.2 3-Methoxyphenyl Phenyl OCH.sub.3      OCH.sub.3 CH O O       I-340 OH Phenyl Methyl OCH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O       I-341 OH 4-Fluorophenyl Methyl OCH.sub.3 OCH.sub.3 CH O O 168(decomp.)        I-342 OH 4-Fluorophenyl Methyl OCH.sub.3 --CH.sub.2 --CH.sub.2      --CH.sub.2       --C O O                                                        I-343      NH--SO--C.sub.6 H.sub.5 4-Nitrophenyl Phenyl OCH.sub.3 OCH.sub.3 CH O O        I-344 OCH.sub.3 Phenyl 3-Imidazolyl OCH.sub.3 --O--CH.sub.2 --CH.sub.2 O       O       I-345 OC.sub.2 H.sub.5 Phenyl 4-Imidazolyl OCH.sub.3 CF.sub.3 N S O           I-346 ON(CH.sub.3).sub.2 Phenyl 2-Pyrazolyl OCH.sub.3 OCF.sub.3 N O S       I-347 ON═C(CH.sub.3).sub.2 2-Hydroxyphenyl Phenyl OCH.sub.3      CH.sub.3 N O O       I-348 NH--SO.sub.2 --C.sub.6 H.sub.5 3-Trifluoromethylphenyl Phenyl      OCH.sub.3 Cl N O O       I-349 NHPhenyl 4-Dimethylaminophenyl Phenyl OCH.sub.3 OCH.sub.3 CH S O        I-350 ONa Phenyl Phenyl OCH.sub.3 OCH.sub.3 CH S S       I-351 O--CH.sub.2 --C.tbd.C Phenyl Phenyl OCH.sub.3 OCH.sub.3 N S S           I-352 OH Phenyl Phenyl CF.sub.3 CF.sub.3 CH O S       I-353 OCH.sub.3 Phenyl Phenyl OCF.sub.3 OCF.sub.3 CH O O       I-354 OC.sub.2 H.sub.5 Phenyl 2-Dimethylaminophenyl CH.sub.3 CH.sub.3      CH O O       I-355 ON(CH.sub.3).sub.2 Phenyl 3-Hydroxyphenyl Cl Cl CH O O       I-356 ON═C(CH.sub.3).sub.2 Phenyl 4-Trifluoromethylphenyl OCH.sub.3      --O--CH.sub.2 --CH.sub.2       -- S O                                           I-357 NH--SO.sub.2      --C.sub.6       H.sub.5 Phenyl 2-Oxazolyl OCH.sub.3 CF.sub.3 N S S              I-358      OH Phenyl Methyl CH.sub.3 CH.sub.3 CH O O       I-359 OH Cyclohexyl Methyl OCH.sub.3 OCH.sub.3 CH O O       I-360 OH Cyclohexyl Methyl OCH.sub.3 CH.sub.2 --CH.sub.2 --CH--C O O          I-361 OH Phenyl Methyl N(CH.sub.3).sub.2 N(CH.sub.3).sub.2 CH O O          I-362 OH Phenyl Methyl OCH.sub.3 OCH.sub.3 CH O SO.sub.2       I-363 OH Phenyl Methyl OCH.sub.3 OCH.sub.3 CH O SO.sub.2       I-364 OH 3-F-Phenyl Me OMe OMe CH O O       I-365 OH 3-F-Phenyl Me OMe CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O            I-366 OH 4-F-Phenyl Me OMe CH.sub.2 --CH.sub.2 CH.sub.2 --C O O      142-143               191°       C.                                                   I-367 OH 3-MeO-Phen      yl Me OMe CH.sub.2 --CH.sub.2 --CH.sub.2       --C O O 158-161                          (decomp.)       I-368 OH 3-MeO-Phenyl Me OMe OMe CH O O       I-369 OH 3-MeO-Phenyl Et OMe CH.sub.2 --CH.sub.2 --CH.sub.2 --C O O           I-370 OH Phenyl HO--CH.sub.2 --CH.sub.2 OMe CH.sub.2 --CH.sub.2      --CH.sub.2       --C O O                                                        I-371 OH P      henyl Me NMe.sub.2 NMe.sub.2 N O O 181       I-372 OH Phenyl Me OMe OMe N O O       I-323 OH       I-374 NH--SO.sub.2       -Phenyl Phenyl Me OMe OMe CH O O                      I-375 NH--SO.sub.2       -Me Phenyl Me OMe OMe CH O O       I-376 CH.sub.2 --SO.sub.2       -Phenyl Phenyl Me OMe OMe CH O O               I-377 CH.sub.2       --SO.sub.2       -Me Phenyl Me OMe OMe CH O O                                  I-378      --CN Phenyl Me OMe OMe CH O O       I-379 Tetrazole sic! Phenyl Me OMe OMe CH O O       I-380 NH--SO.sub.2       -Phenyl Phenyl Me OMe OMe CH O O 167                  I-381 N-Methyltetr      azole Phenyl Me OMe OMe CH O O         sic!       I-382 ONa Phenyl Me OMe --O--CH.sub.2 --CH.sub.2       --C-- O O 122-139(zers.)       I-383 OH o-F-Phenyl Me OMe --O--CH.sub.2 --CH.sub.2 --C-- O O   140-144               (decomp.)       I-384 OH m-Me-Phenyl Me OMe OMe CH O O   169-177       I-385 OH m-Me-Phenyl Me OMe --O--CH.sub.2 --CH.sub.2 --C-- O O 119-135                (decomp.)       I-386 OH p-F-Phenyl Me OMe Me CH O O 137-140               (decomp.)       I-387 OH m-F-Phenyl Me Me --O--CH.sub.2 --CH.sub.2 --C-- O O 150-152          I-388 OH p-F-Phenyl Me Me --O--CH.sub.2 --CH.sub.2 --C-- O O      169-170

                                      TABLE II     __________________________________________________________________________     1 #STR15##     No. R.sup.1            A    R.sup.6      R.sup.2                                 R.sup.3   X  Y Z m.p.  ° C.!     __________________________________________________________________________     II-1         OH Bond Methyl       OMe                                 OMe       CH O O 96-98     II-2         OH CH.sub.2                 Methyl       OMe                                 OMe       CH O O     II-3         OH CH.sub.2 --CH.sub.2                 Methyl       OMe                                 OMe       CH O O     II-4         OH CH═CH                 Methyl       OMe                                 OMe       CH O O     II-5         OH O    Methyl       OMe                                 OMe       CH O O     II-6         OH S    Methyl       OMe                                 OMe       CH O O     II-7         OH NH(CH.sub.3)                 Methyl       OMe                                 OMe       CH O O     II-8         OH Bond Isopropyl    OMe                                 OMe       CH O O 137-139     II-9         OH Bond p-Isopropylphenyl                              OMe                                 OMe       CH O O      II-10         OH Bond Benzyl       OMe                                 OMe       CH O O      II-11         OH CH═CH                 Ethyl        OMe                                 OMe       CH O O      II-12         OH CH═CH                 (CH.sub.3).sub.2 --CH.sub.2 --CH.sub.2                              OMe                                 OMe       CH O O      II-13         OH CH═CH                 Cyclopropylmethylene  sic!                              OMe                                 OMe       CH O O      II-14         OH CH═CH                 Methyl       OMe                                 O--CH.sub.2 --CH.sub.2 --C                                              O O      II-15         OH CH.sub.2 --CH.sub.2                 Ethyl        OMe                                 O--CH═CH--C                                              O O      II-16         OH CH.sub.2 ═CH.sub.2                 Methyl       OMe                                 CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                              O O      II-17         OH Bond Methyl       OMe                                 CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                              O O 147     __________________________________________________________________________

Example 35

Receptor binding data were measured by the binding assay described above for the compounds listed below. The results are shown in Table 2 sic!.

                  TABLE 2  sic!     ______________________________________     Receptor binding data (K.sub.i values)     Compound        ET.sub.A  nM!                                 ET.sub.B  nM!     ______________________________________     I-2             6           34     I-29            86          180     I-5             12          160     I-4             7           2500     I-87            1           57     I.89            86          9300     I-103           0.4         29     I-107           3           485     I-12            19          1700     I-26            23          2000     I-23            209         1100     I-47            150         1500     I-60            33          970     I-96            0.6         56     II-3            107         7300     II-1            28          2300     ______________________________________ 

We claim:
 1. A compound of the formula I ##STR16## where R is formyl, tetrazole, nitrile, a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:R² hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio; R³ hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, NH--O--C₁ -C₄ -alkyl, C₁ -C₄ -alkylthio or CR³ is linked to CR¹⁴ as indicated above to give a 5- or 6-membered ring; R⁴ and R⁵ , which can be identical or different, are phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; orphenyl or naphthyl, which are connected together in the ortho position via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group; or C₃ -C₇ -cycloalkyl; R⁶ hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl, C₃ -C₈ -alkylcarbonylalkyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, phenyl or phenoxy which is substituted one or more times by halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio;phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino or dioxomethylene or dioxoethylene; a five or six-membered heteroaromatic moiety containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; Y sulfur or oxygen or a single bond; Z sulfur, oxygen, --SO-- or --SO₂ --.
 2. The compound of the formula I as defined in claim 1, wherein X is CR¹⁴ and R¹⁴ is hydrogen.
 3. The compound of the formula I as defined in claim 2, wherein R is CO₂ H.
 4. The compound of the formula I as defined in claim 2, wherein R² and R³ each is methoxy.
 5. The compound of the formula I as defined in claim 2, wherein R⁴ and R⁵ each is phenyl.
 6. The compound of the formula I as defined in claim 2, wherein R⁶ is C₁ -C₈ -alkyl.
 7. The compound of the formula I as defined in claim 2, wherein Y is oxygen.
 8. The compound of the formula I as defined in claim 2, wherein Z is oxygen or sulfur.
 9. The compound of the formula I as defined in claim 8, wherein Z is oxygen.
 10. The compound of the formula I as defined in claim 1, whereinX is CH, Y is oxygen, Z is oxygen, R is CO₂ H, R² is methoxy, R³ is methoxy, R⁴ is phenyl, R⁵ is phenyl, R⁶ is methyl, ethyl or iso-propyl.
 11. The compound of the formula I as defined in claim 1, wherein R is tetrazole, nitrile or a group ##STR17## where R¹ has the following meanings: a) hydrogen;b) succinylimidoxy; c) a five-membered heteroaromatic ring linked by a nitrogen atom, selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which ring can carry one or two halogen atoms and or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio; d) a radical ##STR18## where m is 0 or 1 and R⁷ and R⁸, which can be identical or different, have the following meanings:hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl, where these alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry one to five halogen atoms and/or one or two of the following groups: C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkenylthio, C₃ -C₆ -alkynyloxy or C₃ -C₆ -alkynylthio, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl, C₃ -C₆ -alkenylcarbonyl, C₃ -C₆ -alkynylcarbonyl, C₃ -C₆ -alkenyloxycarbonyl or C₃ -C₆ -alkynyloxycarbonyl, phenyl, which can be substituted one or more times by halogen, nitro, cyano, C₃ -C₆ -alkenylcarbonyl, C₃ -C₆ -alkynylcarbonyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, di-C₁ -C₄ -alkylamino, orR⁷ and R⁸ together form a C₄ -C₇ -alkylene chain which can be substituted by C₁ -C₄ -alkyl, and may contain a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or R⁷ and R⁸ together form a CH₂ --CH═CH--CH₂ or CH═CH--(CH₂)₃ chain; e) a radical ##STR19## where k is 0, 1 and 2, p is 1, 2, 3 and 4, and R⁹ is C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or phenyl, which can be substituted one or more times by halogen, nitro, cyano, C₃ -C₆ -alkenylcarbonyl, C₃ -C₆ -alkynylcarbonyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio; f) a radical OR¹⁰, where R¹⁰ ishydrogen, the cation of an alkali metal or an alkaline earth metal or an environmentally compatible organic ammonium ion; C₃ -C₈ -cycloalkyl which may carry one to three C₁ -C₄ -alkyl groups; C₁ -C₈ -alkyl which may carry one to five halogen atoms and/ or one of the following radicals: C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, cyano, C₁ -C₄ -alkylcarbonyl, C₃ -C₈ -cycloalkyl, C₁ -C₄ -alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aromatic radicals in turn may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; C₁ -C₈ -alkyl which may carry one to five halogen atoms and which carries one of the following radicals: a 5-membered heteroaromatic ring containing one to three nitrogen atoms or a nitrogen atom and an oxygen or sulfur atom, which may carry one to four halogen atoms and/or one or two of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; C₂ -C₆ -alkyl which carries one of the following radicals in position 2: C₁ -C₄ -alkoxyimino, C₃ -C₆ -alkynyloxyimino, C₃ -C₆ -haloalkenyloxyimino or benzyloxyimino; C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl which may carry one to five halogen atoms; phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; a 5-membered heteroaromatic ring which is bonded via a nitrogen atom and containing one to three nitrogen atoms, which may carry one or two halogen atoms and or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; a radical ##STR20## where R¹ and R¹², which may be identical or different are: C₁ -C8-alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; phenyl which may carry one or more of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio; or R¹¹ and R¹² together form a C₃ -C₁₂ -alkylene chain which may carry one to three C₁ -C₄ -alkyl groups and which may contain a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur; g) a radical ##STR21## where R¹³ is C₁ -C₄ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or a phenyl radical, orphenyl which may carry one or more of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio. 